A medication prescribed for schizophrenia and manic phases of bipolar disorder shows promise as a cocaine addiction treatment.

By LORI WHITTEN, NIDA Notes Staff Writer

The antipsychotic medication aripiprazole appears to reduce cocaine craving in small studies of addicted individuals with schizophrenia and bipolar disorder. A recent NIDA-funded experiment suggests that aripiprazole may help not only those very-difficult-to-treat individuals, but others as well, to maintain abstinence from the stimulant.

Drs. Ronald See and Matthew Feltenstein of the Medical University of South Carolina found that rats treated with aripiprazole were less likely than untreated rats to resume cocaine self-administration after a period of abstinence. The finding indicates that the medication reduces cocaine seeking directly rather than as a byproduct of altering psychotic symptoms or processes. Therefore, the researchers speculate, cocaine abusers who do not have concurrent psychotic illness may also benefit from aripiprazole.

INDIFFERENCE TO COCAINE WITH FEW SIDE EFFECTS

The researchers subjected rats to a protocol that simulates drug use, followed by the establishment of stable abstinence, and finally a test of the animals' vulnerability to relapse. Animals that are vulnerable respond to a relapse trigger—a cocaine-associated cue or a priming dose of the drug—by pressing a lever they previously used to self-administer the drug. The more vulnerable an animal is, the more often it will press the lever.

ARIPIPRAZOLE ALLEVIATES DOPAMINE IMBALANCE THAT PROMOTES RELAPSE According to researchers, cocaine relapse may be fostered by high dopamine concentrations in the nucleus accumbens, one of the brain's reward centers, and low concentrations in the prefrontal cortex. Aripiprazole simultaneously blocks dopamine receptors (left) in brain regions with high concentrations of the neurochemical and stimulates receptors (right) in regions where concentrations are low.

Rats given the lowest effective dose of aripiprazole (0.25 mg/kg) before the priming dose of cocaine pressed the lever associated with cocaine 50 percent as often as control rats did. The higher the dose of aripiprazole, the less the rats responded to the relapse triggers. For example, after the drug trigger, rats given the highest dose of aripiprazole (15 mg/kg) pressed the lever associated with cocaine only 9 percent as often as the rats receiving no aripiprazole.

To rule out the possibility that aripiprazole reduced the rats' cocaine seeking through general effects—such as sedation or lethargy—that would be undesirable in a medication, the investigators conducted further trials that showed:

• Aripiprazole does not sedate animals to the point where they are too tired to approach and press levers for rewards. During the protocol that mimicked relapse, the lowest medication doses that attenuated lever pressing did not suppress locomotor activity. Higher doses (1 mg/kg and 5 mg/kg) reduced spontaneous and cocaine-induced locomotor activity only modestly. Furthermore, while aripiprazole-treated rats pressed the drug-linked lever less often, they continued to press another lever, which delivered nothing at all, as often as before.
• Aripiprazole does not make rats indifferent to rewards from all activities, including natural, healthy ones. Aripiprazole did not reduce the enthusiasm with which rats pressed levers to obtain food, so it did not seem to blunt their natural pleasure responses. In addition, when the researchers put animals through a protocol that simulates ongoing drug use, rather than recovery from an addiction, the animals pressed levers to obtain cocaine infusions just as avidly after receiving aripiprazole as after saline. This result indicates that while the medication may help individuals maintain abstinence, it is unlikely to diminish ongoing binge cocaine abuse.

"Aripiprazole's minimal effect on rats' motor activity and other behaviors is consistent with its good safety profile and general acceptance among patients as a psychiatric medication," says Dr. See. "We find it encouraging that low doses block drug seeking and seem to have no other discernible effects on the animals. Taken together, our findings suggest that aripiprazole may selectively reduce drug-seeking behavior and is a promising candidate medication for preventing cocaine relapse."

A SELECTIVE STABILIZER

Dr. See and colleagues focused on aripiprazole for practical reasons: It is generally safe, it is already on the market, and its pharmacological action suggests the potential to reduce relapse. Aripiprazole preferentially binds to dopamine receptors D₂ and D₃, which are proteins on brain cell surfaces that mediate dopamine's effects on cellular activity. The drug has different effects, depending on the amount of dopamine present. The overall effect is neurochemical modulation: Aripiprazole quiets hyperactive neurons and stimulates sluggish ones through both presynaptic and postsynaptic mechanisms, according to Dr. See. Such stabilization seems to account for the efficacy of aripiprazole as a psychiatric medication and may also underlie its benefit as a relapse-prevention agent.

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"As a neurochemical stabilizer, aripiprazole most likely reduces excess dopamine activity in the mesolimbic reward circuit brought about by drug abuse," says Dr. See. "The medication also may simultaneously boost dopamine in the cortex, particularly the prefrontal circuits, thereby enhancing the ability to suppress the desire for drugs." Although aripiprazole also acts at serotonin receptors, pharmacologists currently consider dopamine stabilization to be its main therapeutic action.

To evaluate the full extent of aripiprazole's promise, it must still be determined whether the medication could be used to treat addiction to other psychostimulants besides cocaine, notes Dr. Cora Lee Wetherington of NIDA's Division of Basic Neuroscience and Behavioral Research. Dr. See notes that his team plans to perform animal tests of the drug's effect on methamphetamine.

With regard to cocaine, Dr. Wetherington says, "the results of Dr. See's animal study suggest that aripiprazole may help prevent relapse in cocaine abusers both with and without psychiatric conditions. The work lays the groundwork for future clinical research."

Says Dr. See, "We hope to use brain imaging to examine aripiprazole's effects on cocaine abusers' responses to drug cues—to find out whether it dampens brain activity related to such cues. If so, that would also support the idea that the medication helps prevent relapse."

SOURCE

Feltenstein, M.W., Altar, C.A., and See, R.E. Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse. Biological Psychiatry 61(5):582-590, 2007. [Abstract]

Volume 22, Number 2 (December 2008)